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Current Research and Scholarly Interests

My area of research interest is focused on the epidemiology, pathophysiology, prevention, and treatment of infections in children. Much of my research experience has focused on viral infections, especially those caused by herpes simplex virus (HSV). I have conducted a number of studies concerned with the epidemiology of HSV-2 infections in pregnant women, their partners, and neonates. Recently, I have extended these epidemiologic studies to adolescents. I have also conducted studies on the immunologic response to HSV infections, including humoral and cell mediated responses. Furthermore, I have participated in a number of studies evaluating optimal therapy of HSV infections in pregnant women and neonates and HSV vaccine protocols. My interest in antiviral therapy extends beyond HSV infections; I have been involved in a number of studies of therapy for respiratory viral and HIV infections. My interest in bacterial infections includes the evaluation of a number of antibacterial agents (Phase I-III studies). I also am interested in the evaluation and management of infections in compromised hosts including neonates, transplant and chemotherapy recipients. I also am interested in developing interventions to reduce the inappropriate utilization of antimicrobial agents in ambulatory and hospital environments.I am keenly interested in medical education at the undergraduate, medical school, residency, and fellowhsip level. My educational focus has centered on microbiology and infectious diseases and on the education of clinical research scientists.

Abstract

Recent studies suggest that students' feelings of fit with a residency program substantially influence students' ranking of the program. As diversity issues become increasingly focal concerns, we investigate how perception of gender and racial diversity of a program influences students' rankings of the program. We focus on students pursuing surgical specialties and ask whether diversity concerns are more prominent among applicants to surgical programs than among applicants to nonsurgical programs.We invited all interviewees at all residency programs at the Stanford University School of Medicine to participate in our study in the spring of 2009. Nineteen residency programs, amounting to 1,657 residency interviewees, participated. Sixty-eight percent (n = 1,132) responded to the survey.Women and under-represented minority applicants differ in their assessments from male and non-under-represented minority applicants because women applying to surgical programs and under-represented minority students are less likely than others to perceive their prospective programs as diverse. However, perceived program diversity is an important factor that positively influences the program ranking decision for women and minorities pursuing surgical training.Surgical training programs that promote gender and racial diversity will likely be more successful in attracting women and minority students because women and minorities are especially sensitive to program diversity in both their perceptions and rankings of programs. Promoting women and minorities within programs and connecting women and minority applicants to outreach programs and mentors is pertinent to the recruitment of these traditionally under-represented groups to surgical programs.

Commentary: To Genotype or Not to Genotype? Addressing the Debate Through the Development of a Genomics and Personalized Medicine CurriculumACADEMIC MEDICINESalari, K., Pizzo, P. A., Prober, C. G.2011; 86 (8): 925-927

Abstract

As technologic innovation helps broaden and refine our knowledge base of genetic associations, a growing interest in translating these genetic discoveries to clinically useful laboratory tests has given rise to the potential of personalized medicine. To fully realize this potential, medical schools must educate trainees on genetic and genomic testing in clinical settings. An emerging debate in academic medical centers is not about the need for this education but, rather, the most effective educational models that should be deployed. At Stanford School of Medicine, several proposals to offer personal genotyping in the educational curriculum argued that learning genetics and the attendant cutting-edge molecular techniques would be more powerful and sustained if students were applying their knowledge to their personal genotypes. Given the complex ethical, legal, and social issues involved in implementing such a program, a schoolwide task force was formed to evaluate the risks and benefits of offering personal genotyping to students and residents. In this commentary, the authors discuss the salient issues raised by the task force and describe the safeguards adopted into the ultimate approval and implementation of the course, which included the opportunity for students to analyze their own genomes.

Abstract

Over the past 20 years, the use of zinc as an over-the-counter alternative therapy for the common cold has vastly grown in popularity. Recent reports of potentially permanent anosmia caused by intranasal zinc therapy warrant careful analysis of the therapeutic effects of zinc.A search of the Medline database (including articles published during 1966-2006) for studies of zinc and the common cold produced 105 published reports. Fourteen were randomized, placebo-controlled studies that examined the effect of zinc lozenges, nasal sprays, or nasal gels on naturally acquired common colds. Eleven features of experimental design affecting signal quality, chance, bias, and blinding were used to evaluate the 14 placebo-controlled studies. These criteria were validated case definition, quantifiable hypothesis, sample size calculation, randomized assignment, double blinding, proof of blinding, measurement of compliance, measurement of dropout rate, analysis by intent to treat, description of methods of analysis, and measurements of probability. Equal weight was given to each criterion, because failure to meet any one could potentially invalidate the findings of a clinical trial.Four studies met all 11 criteria. Three of these studies reported no therapeutic effect from zinc lozenge or nasal spray. One study reported positive results from zinc nasal gel. Of the remaining 10 studies, 6 reported a positive effect and 4 reported no effect. Intent-to-treat analysis was the most common criterion not met.This structured review suggests that the therapeutic effectiveness of zinc lozenges has yet to be established. One well-designed study did report a positive effect of zinc nasal gel.

Abstract

Neonatal herpes simplex virus (HSV) is a rare but devastating disease. We have conducted pooled analyses of data from 3 cohorts to evaluate the effects of maternal HSV serostatus and HSV type on risk of neonatal HSV acquisition and severity.Data from cohorts in Seattle, WA, and Stanford, CA, USA, and Stockholm, Sweden were pooled using Mantel-Haenszel methods.Seventy-eight infants with documented neonatal HSV and known maternal HSV serostatus were included. The risk of neonatal HSV-2 infection was similar in infants born to HSV seronegative women compared with HSV-1 seropositive women (pooled OR: 1.6; 95% CI: 0.6-4.0). The odds of neonatal HSV infection was increased in the presence of exposure to maternal HSV-1 versus HSV-2 (adjusted pooled OR: 19.2; 95% CI: 5.8-63.6). An elevated odds of disseminated HSV in infants born to women with newly acquired genital herpes was observed in Stockholm (OR=13.5; 95% CI: 1.4-630), but not in Seattle or Stanford.Our results suggest that maternal HSV-1 antibody offers little, if any, protection against neonatal HSV-2 infection. During reactivation, HSV-1 appears more readily transmissible to the neonate than HSV-2, a concerning finding given the rising frequency of genital HSV-1 infection.

Abstract

The objective of the study was to assess whether herpes simplex virus antibody avidity is associated with risk of transmission of herpes simplex virus to the neonate.We developed a novel herpes simplex virus type 1 avidity test based on the commercially available Focus HerpeSelect-1 enzyme-linked immunosorbent assay kit using sera from nonpregnant subjects with genital herpes simplex virus-1 infection. We used this test, and the previously developed herpes simplex virus type 2 avidity test, to compare maternal herpes simplex virus-1 and herpes simplex virus-2 antibody avidity in women who transmitted herpes simplex virus to the neonate and women who had herpes simplex virus isolated from genital secretions at delivery but who did not transmit herpes simplex virus to their infants.Among nonpregnant subjects with genital herpes simplex virus-1 infection whose sera were used to develop the herpes simplex virus-1 avidity test, a significant relationship between herpes simplex virus-1 antibody avidity and time since herpes simplex virus-1 acquisition was observed (P < .001, mixed-effects model), with median avidity values increasing over time after primary infection. Among pregnant, herpes simplex virus-1, or herpes simplex virus-2 seropositive women, 4 of 8 women (50%) with avidity 40 or greater transmitted herpes simplex virus to the neonate, compared with only 12 of 97 (12%) of women with avidity greater than 40 (P = .02).Herpes simplex virus-1 antibody avidity increased over time after genital herpes simplex virus-1 acquisition, as has been previously observed for herpes simplex virus-2. Among women with herpes simplex virus antibody at delivery, low antibody avidity was associated with herpes simplex virus transmission to the neonate and may be a useful marker for recent seroconversion.

Abstract

Varicella zoster virus (VZV), herpes simplex virus (HSV) and cytomegalovirus (CMV) are all members of the Herpesviridae family.Humans are the only source of infection for these double stranded DNA viruses. Infants may acquire these infections in utero, peripartum, or postnatally, resulting in a variety of clinical syndromes, ranging from asymptomatic infection to severe infection,with high mortality rates and significant long-term morbidity. This article presents the epidemiology, clinical characteristics, treatment,and prevention strategies for VZV, HSV, and CMV infections in infants.

Abstract

Palivizumab and Respiratory Syncytial Virus Immune Globulin Intravenous (RSV-IGIV) are licensed by the Food and Drug Administration for use in preventing severe respiratory syncytial virus (RSV) infections in high-risk infants, children younger than 24 months with chronic lung disease (formerly called bronchopulmonary dysplasia), and certain preterm infants. This report summarizes the clinical trial information on which the guidance in the accompanying policy statement for administering RSV prophylaxis to certain children with a history of preterm birth, chronic lung disease, or congenital heart disease is based. On the basis of results of a recently completed clinical trial, palivizumab is appropriate for infants and young children with hemodynamically significant congenital heart disease. RSV-IGIV should not be used in children with hemodynamically significant heart disease. Palivizumab is preferred for most high-risk infants and children because of ease of intramuscular administration. Monthly administration of palivizumab during the RSV season results in a 45% to 55% decrease in the rate of hospitalization attributable to RSV. Because of the large number of infants born after 32 to 35 weeks' gestation and because of the high cost, immunoprophylaxis should be considered for this category of preterm infants only if 2 or more risk factors are present.

Abstract

A small number of antiviral drugs are available for the treatment of varicella zoster virus (VZV) and herpes simplex virus (HSV) infections in children. This review presents pharmacokinetic data on the following selected antiviral agents: aciclovir, valaciclovir, famciclovir, cidofovir and foscarnet. Support and current recommendations for the treatment of selected VZV and HSV infections in children will also be reviewed.

Abstract

Epidemiologic studies indicate that children with certain chronic conditions, such as asthma, and otherwise healthy children younger than 24 months are hospitalized for influenza and its complications at high rates similar to those experienced by the elderly. Currently, annual influenza immunization is recommended for all children 6 months and older with high-risk conditions. To protect these children more fully against the complications of influenza, increased efforts are needed to identify and recall high-risk children for annual influenza immunization. In addition, immunization of children 6 through 23 months of age and their household contacts and out-of-home caregivers is now encouraged to the extent feasible. The ultimate goal is a universal recommendation for influenza immunization. Issues that need to be addressed before institution of routine immunization of healthy young children include education of physicians and parents about the morbidity caused by influenza, adequate vaccine supply, and appropriate reimbursement of practitioners for influenza immunization.

Abstract

After an extensive worldwide eradication program, the last nonlaboratory case of smallpox occurred in 1977 in Somalia. In 1972, routine smallpox immunization was discontinued in the United States, and since 1983, vaccine production has been halted. Stockpiled vaccine has been used only for laboratory researchers working on orthopoxviruses. In recent years, there has been concern that smallpox virus stocks may be in the hands of bioterrorists, and this concern has been heightened by the terrorist attack on the World Trade Center and the Pentagon on September 11, 2001. Because most of the population is considered to be nonimmune, there is debate as to whether smallpox immunization should be resumed. This statement reviews the current status of smallpox vaccine, the adverse effects that were associated with smallpox vaccine in the past, and the major proposals for vaccine use. The statement provides the rationale for a policy based on the so-called ring vaccination strategy recommended by the Centers for Disease Control and Prevention, in which cases of smallpox are rapidly identified, infected individuals are isolated, and contacts of the infected individuals as well as their contacts are immunized immediately.

Abstract

Approximately 2000 neonates contract infection due to herpes simplex virus each year in the United States. Although herpes simplex virus type 2 is responsible for most neonatal infections, approximately 30% of infections are caused by herpes simplex virus type 1. Infections are categorized by extent of disease into skin/eye/mouth, central nervous system and disseminated disease categories. Each disease category is responsible for roughly one third of neonatal infections. Mortality is highest in disseminated disease. Morbidity is highest for survivors of central nervous system infection. Treatment with high dose parenteral acyclovir (60 mg/kg/day) for 14-21 days improves outcome. Since most neonatal infections are acquired from contact with infected maternal genital tract secretions, potential preventative strategies include: Caesarean delivery, serologic screening of pregnant women, prophylactic acyclovir and vaccination. The two strategies currently accepted by most obstetricians are Caesarean delivery for women with active lesions or prodromal symptoms and prophylactic acyclovir for women with gestational herpes.

Abstract

Every year, influenza viruses cause global epidemics that result in significant morbidity and mortality. Influenza infections can be serious in children, especially infants and toddlers. Four antiviral agents, amantadine, rimantadine, oseltamivir, and zanamivir, are available for the treatment or prophylaxis of influenza. Experience with the use of these antiviral drugs for influenza in children is limited. Given the small degree of therapeutic gain that is reported from clinical trials, considerations about cost effectiveness are important in deciding whether to use these agents in the treatment of suspected or proven influenza infections in healthy children.

Abstract

In 1998, the Food and Drug Administration (FDA) approved the licensure of tobramycin solution for inhalation (TOBI). Although a number of additional antibiotics, including other aminoglycosides, beta-lactams, antibiotics in the polymyxin class, and vancomycin, have been administered as aerosols for many years, none are approved by the FDA for administration by inhalation. TOBI was approved by the FDA for the maintenance therapy of patients 6 years or older with cystic fibrosis (CF) who have between 25% and 75% of predicted forced expiratory volume in 1 second (FEV(1)), are colonized with Pseudomonas aeruginosa, and are able to comply with the prescribed medical regimen. TOBI was not approved for the therapy of acute pulmonary exacerbations in patients with CF nor was it approved for use in patients without CF. Currently, no other antibiotics are approved for administration by inhalation to patients with or without CF. The purpose of this statement is to briefly summarize the data that supported approval for licensure of TOBI and to provide recommendations for its safe use. The pharmacokinetics of inhaled aminoglycosides and problems associated with aerosolized antibiotic treatment, including environmental contamination, selection of resistant microbes, and airway exposure to excipients in intravenous formulations, will be discussed.

Abstract

The cephalosporins are the largest and most diverse family of antimicrobial agents available. Although they rarely are considered drugs of first choice for the therapy of bacterial infections, they are the most commonly prescribed agents for both ambulatory and hospitalized patients. The first-generation agents have the most limited spectrum of bactericidal activity, but they are the most potent against Gram-positive microbes. The third- and fourth-generation agents have a broad spectrum of activity that includes the majority of Gram-negative pathogens. However, they are less active than their first-generation counterparts against Gram-positive bacteria, especially S aureus. The cephalosporins generally are well tolerated, and the oral agents are palatable. However, their use is limited by increasing resistance among certain groups of bacteria and high cost, especially of the parenteral and recently licensed oral agents. The prudent physician need not be familiar with all cephalosporins, but should be knowledgeable about a select few.

Abstract

Acute viral encephalitis and postinfectious encephalomyelitis affect both children and adults. Enteroviruses, HSV types 1 and 2, and arboviruses are the most common causes of encephalitis in the United States; however, the differential diagnosis is broad. History taking and physical examination can provide clues to the cause, but the diagnosis is usually established on the basis of CSF analysis, viral culture, MRI, and serologic testing, when indicated. In the future, PCR techniques may enhance rapidity of diagnosis. Until the specific cause is identified, empirical therapy should be given. Because complications can be severe, all patients with encephalitis should be monitored in a facility capable of providing supportive intensive care. Long-term follow-up is important to detect sequelae, particularly in patients with eastern equine or HSV encephalitis.

Abstract

To determine if the signs and symptoms of genital herpes in pregnancy accurately identify primary genital herpes infections using serologic testing for final classification.Twenty-three women with clinical signs and symptoms suggestive of primary genital herpes infections in the second and third trimesters of pregnancy were subsequently cultured and tested serologically (for herpes simplex virus type 1 and herpes simplex virus type 2 antibodies) and classified as having true primary (no herpes simplex virus type 1 or type 2 antibodies), nonprimary (heterologous herpes simplex virus antibodies present), or recurrent (homologous antibodies present) infections.Only one of 23 women with clinical illnesses consistent with primary genital herpes virus simplex infections had serologically-verified primary infection. This primary infection was caused by herpes simplex virus type 1. Three women had nonprimary type 2 infections, and 19 women had recurrent infections. Among culture-proven recurrent infections, 12 were caused by herpes simplex virus type 2 and three by herpes simplex virus type 1. Only one infant was born preterm, and no clinically significant perinatal morbidity was observed.Correct classification of gestational genital herpes infections can be accomplished only when clinical evaluation is correlated with viral isolation and serologic testing using a type-specific assay. Severe first episodes of genital herpes infections among women in the second and third trimesters of pregnancy are not usually primary infections and are not commonly associated with perinatal morbidity.

Abstract

Cerebrospinal fluid (CSF) specimens from 77 neonates with herpes simplex virus (HSV) disease were evaluated retrospectively by polymerase chain reaction (PCR). Samples were collected from 202 infants enrolled in a National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group trial that compared vidarabine with acyclovir for the treatment of neonatal HSV infection. HSV DNA was detected in the CSF of 26 (76%) of 34 infants with CNS disease, in 13 (93%) of 14 infants with disseminated infection, and in 7 (24%) of 29 with skin, eye, or mouth (SEM) involvement. One of the 7 PCR-positive SEM patients subsequently developed severe neurologic impairment. Eighteen (95%) of 19 infants with positive CSF PCR results after the completion of 10 days of antiviral therapy experienced significant morbidity or mortality. Application of PCR to neonatal HSV disease may provide additional information on which clinical decisions may be based, although its diagnostic utility outside the research setting is unproven.

Abstract

T cell recognition of common and type-specific herpes simplex virus (HSV) glycoproteins was measured in 72 subjects. T cells were stimulated with whole HSV-2 antigen and glycoproteins gB2, gD2, and gG2. T cell proliferation in response to HSV-2 antigen and gG2 was significantly higher in subjects with HSV-2 infection than in those with HSV-1 infection only; responses to gB2 and gD2 were the same. T helper (Th) type 1 and Th2 cytokine production in response to whole HSV-2 antigen, gB2, and gD2 was evaluated in 33 subjects. Interleukin (IL)-2 and interferon-gamma responses to most antigens were significantly higher among HSV-2-seropositive subjects than among seronegative subjects. IL-4 synthesis was negligible; IL-10 was produced in seronegative and seropositive persons, but HSV-2 antigen responses were significantly higher in HSV-2-seropositive persons. Naturally acquired immunity to HSV involves T cell recognition of common and type-specific glycoproteins, prominent Th1 responses, and discordant Th2 responses with little IL-4 but substantial IL-10 production.

Abstract

Early diagnosis and treatment of septic arthritis improves the potential for a favourable outcome. Optimal treatment includes the prompt and judicious use of effective antimicrobial agents coupled with prompt drainage of the affected joint. Adequate drainage may be accomplished by means of repeated closed large-bore needle aspiration, arthroscopy, or an open surgical procedure. The purpose of this article is to describe optimal antimicrobial therapy based upon available pharmacokinetic data. The host-dependent vulnerability to specific pathogens, local antibacterial susceptibility patterns and knowledge of antibacterial activity at the site of infection must all be taken into account when planning appropriate treatment. This article does not address arthritis secondary to human and animal bites, diabetic foot infections, mycobacteria, fungi, Lyme spirochaete, or other nonbacterial causes of septic arthritis.

Abstract

The seroprevalence of infection with type 2 herpes simplex virus (HSV-2) was determined in 135 adolescents detained in a juvenile detention facility. A total of 16% of enrollees were seropositive for HSV-2. Age of onset of sexual intercourse, number of lifetime partners, frequency of condom use, and history of sexually transmitted diseases did not predict HSV-2 seropositivity.

Abstract

To describe our experience with developing, implementing, and evaluating the educational effect of a school health experience for pediatric residents.Descriptive.University-based pediatric residency program and five public elementary and middle schools in surrounding communities.Eleven pediatric residents.A school health experience for pediatric residents was developed in response to the report of the American Academy of Pediatrics Task Force on Pediatric Education and the new training recommendations of the Residency Review Committee of the American Council for Graduate Medical Education. Residents spent 3 weeks in the schools engaged in teaching and observational activities.Questionnaires of residents' attitudes and knowledge, structured resident interviews, and teacher questionnaires.Positive effect on resident's knowledge of school structure, child development, communication with children, school-related problems, and special education. Positive effects on resident's attitudes about teamwork between teachers and pediatricians and roles of pediatricians in schools. Teacher feedback showed acceptance by the school community.Pediatric residents benefit from exposure to children in school settings. Schools provide an opportunity to observe normal childhood development and behavior in a more natural setting than that provided in the hospital.

Abstract

To describe the progression of human immunodeficiency virus (HIV) disease through clinical stages from birth to death among a large number of perinatally infected children.The Pediatric Spectrum of Disease (PSD) project, coordinated by the Centers for Disease Control and Prevention (CDC), has conducted active surveillance for HIV disease since 1988 in seven geographic regions. PSD data are collected from medical and social service records every 6 months through practitioners at each participating hospital clinic. We analyzed data from perinatally HIV-infected children born between 1982 and 1993. The natural history of HIV disease was divided into five progressive stages using the clinical categories in the CDC 1994 pediatric HIV classification system: stage N, no signs or symptoms; stage A, mild signs or symptoms; stage B, moderate signs or symptoms; stage C, severe signs or symptoms; and stage D, death. A five-stage Markov model was fitted to the PSD data. To compare the estimates from the PSD project with the published estimates, we also fitted an alternative Markov model using acquired immunodeficiency syndrome (AIDS; 1987 case definition) in place of stage C and also calculated standard Kaplan-Meier estimates.A total of 2148 perinatally HIV-infected children were included in the analysis. The estimated mean times spent in each stage were: N, 10 months; A, 4 months; B, 65 months; and C, 34 months. We estimated that a child born with HIV infection has a 50% (95% confidence interval [CI], 40%-60%) chance of severe signs or symptoms developing by 5 years of age and a 75% (95% CI, 68%-82%) chance of surviving to 5 years of age. For a child in stage B, there is a 60% (95% CI, 49%-71%) chance of severe signs or symptoms developing within the next 5 years and a 65% (95% CI, 56%-73%) chance of surviving 5 more years. The estimated mean time from birth to stage C was 6.6 (95% CI, 5.7-7.5) years, and the estimated mean survival time from birth was 9.4 (95% CI, 8.1-10.7) years. From the alternative Markov model, the estimated mean time from birth to AIDS was 4.8 (95% CI, 4.5-5.2) years.Markov modeling using the revised pediatric classification system allowed us to describe the natural history of HIV disease in children before diagnosis of AIDS. On average, children progress to moderate symptoms in the second year of life and then remain moderately symptomatic for more than half of their expected lives, underscoring their need for clinical care before the onset of AIDS. The results from the Markov model are useful in family counseling, health care planning, and clinical trial designs.

Abstract

To assess the effect of cesarean delivery on neonatal and maternal morbidity and mortality and their associated costs for two populations of women presenting with genital herpes lesions at delivery: those with and those without a history of genital herpes.MEDLINE (search for herpes simplex virus and neonatal, cesarean, and mortality) and recognized experts.The quality of the overall data used for baseline values was graded using a predetermined scale.The practice of cesarean delivery for women with a history of genital herpes lesions that recur at delivery results in more than 1580 excess cesarean deliveries performed for every poor neonatal outcome prevented, a cost per neonatal herpes case averted of $2.5 million and a cost per quality-adjusted life-year gained of $203,000. For these women, lowering the efficacy of cesarean delivery or the herpes simplex virus vertical transmission rate could result in maternal deaths outnumbering neonatal deaths prevented. In contrast, cesarean delivery for women with no history of genital herpes simplex virus who have lesions at delivery has low maternal costs per neonatal benefit and saves money.Women who present with their first clinical episode of genital herpes at delivery should have a cesarean section performed. However, the current practice of cesarean delivery for women with a history of genital herpes lesions that recur at delivery results in high maternal morbidity and mortality at substantial financial expense, underscoring the urgency of examining alternative management strategies.

Abstract

Substantial advances have been made in our understanding of HSV and genital herpes. The molecular biology of viral structure and function and the pathogenesis of infection have been elucidated to a large degree, and epidemiologic investigations, based on reliable type-specific assays, have been done. Diagnostic techniques have been refined, and the value of therapy has been defined. Currently, management strategies for pregnant women and their neonates are based on data rather than hypothesis, and rational counseling is feasible. The next major advance in the field would be the availability of a safe and effective vaccine, the development and investigation of which is being pursued vigorously.

Abstract

The gene (US4) coding for herpes simplex virus type 2 (HSV-2) glycoprotein G (gG-2) was cloned and constitutively expressed in Chinese hamster ovary (CHO) cells. The expression vector containing the dihydrofolate reductase (dhfr) gene, and the HSV-2 US4 gene under the control of the Simian virus 40 early promoter (SV40 EP), was transfected into dhfr-deficient CHO cells. The transfected cells were selected and amplified using methotrexate (MTX). To demonstrate that the gG-2 produced in these transformed cells had antigenic determinants in common with the native glycoprotein, CHO cells expressing gG-2 were used in an immunofluorescent assay (IFA) for the detection of HSV-2 type-specific antibodies in human serum samples. Seven of eight serum samples from adults with prior episodes of culture proven HSV-2 infections were found to be positive by the IFA method whereas none of seven serum samples from young children with culture documented HSV-1 infections were positive by IFA. Thus the recombinant CHO : gG-2 cells have diagnostic utility in an HSV-2 specific serologic assay.

Abstract

Neonatal herpes, one of the most feared infections during infancy, continues to command the attention of many investigators. In the past year, important new findings were reported pertaining to epidemiology, diagnosis, prevention, and treatment of this disease. Unfortunately, practical solutions for many clinical problems remain elusive. This review describes recent advances in our understanding of neonatal herpes with particular emphasis on the dilemmas and controversies associated with management and prevention. Although elimination of neonatal herpes remains a distant goal, the review discusses reasons for hope, including improved prevention strategies based on recent epidemiologic data, development of new rapid diagnostic methods, and progress in the quest for an effective vaccine.

Abstract

In this review we summarize current knowledge related to the identification of pregnancies that may be complicated by genital herpes and describe the consequences of maternal infections with genital herpes. We address the implications of this information for the management of genital herpes during pregnancy and at delivery and for the care of neonates exposed to herpes simplex virus at delivery. On the basis of the current data, we cannot make specific recommendations concerning many of the clinical problems that are caused by herpes simplex virus infections in pregnant women. We identify and discuss unresolved questions about optimal management.

Abstract

Primary infections with herpes simplex virus type 2 (HSV-2) acquired by women during pregnancy account for about half of the morbidity and mortality from HSV-2 among neonates. The other half results from reactivation of old infections. Better methods are needed to identify which women are at risk for primary HSV-2 infection.We prospectively studied HSV-2 infections among pregnant women who were patients in private obstetrical practices. Using an enzyme-linked immunosorbent assay that detects type-specific antibodies to HSV-2 glycoprotein G, we determined the prevalence at base line of HSV-2 infections among pregnant women and their husbands, the frequency of discordance for infection between partners, and the risk of seroconversion during pregnancy among the seronegative women whose husbands were seropositive.The seroprevalence of HSV-2 was 32 percent among the 277 women followed throughout their pregnancies and 25 percent among the 190 husbands studied. Two thirds of the HSV-2-seropositive women had no history of genital herpes. Of the 190 couples, 139 (73 percent) were serologically concordant for HSV-2 antibodies (57 percent being seronegative and 16 percent being seropositive), whereas 51 couples (27 percent) were discordant, despite having been sexually intimate for a mean of 6.1 years. Eighteen women who were seronegative for HSV-2 (9.5 percent) had seropositive partners, of whom 10 (56 percent) had no history of genital herpes. Thus, approximately 5 percent of these pregnant women had an unsuspected risk of contracting a primary HSV-2 infection. One of the 18 seronegative women with a seropositive husband seroconverted to HSV-2 during pregnancy; none of the other women seroconverted.In this study about 10 percent of pregnant women were at risk of contracting a primary HSV-2 infection from their HSV-2-seropositive husbands. In addition, about a third of these women were seropositive for HSV-2 and thus at risk for asymptomatic, reactivated infections. Serologic testing of couples can identify women who are at risk for primary or reactivated HSV-2 infections during pregnancy.

Abstract

Respiratory syncytial virus is the major respiratory pathogen in infants and young children. Every year, this unique and ubiquitous virus accounts for substantial morbidity and occasional mortality in this age group. Until recently, therapy for respiratory syncytial virus infections was limited to supportive measures such as hydration, supplemental oxygen, and assisted ventilation. Therefore, the licensure of ribavirin in 1986 for treatment of respiratory syncytial virus infections raised hopes for specific and effective therapy. However, the use of ribavirin has been the subject of continuing controversy and debate. Despite at least eight controlled clinical trials involving collectively over 170 patients treated with ribavirin since 1983, no clear consensus has developed regarding which patients should be treated with ribavirin. Major issues are weaknesses in the design and methodology of studies that claim treatment efficacy, the clinical significance of the demonstrated treatment effects, potential teratogenicity to health care workers exposed to aerosolized ribavirin, and cost-effectiveness of the intervention. This review will explore each of these areas of controversy and consider the unanswered questions to which future research must be directed.

Abstract

To determine whether orally administered acyclovir is of therapeutic benefit for varicella in otherwise healthy adolescents, and to compare the severity of the disease in adolescents with that in younger children.Multicenter, randomized, placebo-controlled, double-blind trial.Patients' homes and university hospital clinics.Sixty-eight adolescents between 13 and 18 years of age with varicella entered the study. Of the 62 adolescents with laboratory-confirmed varicella who were included in the final analysis, 31 received acyclovir and 31 received placebo.Placebo or an 800 mg acyclovir tablet was given orally four times daily for 5 days, beginning within 24 hours of onset of rash.Acyclovir recipients had significant reductions in times to cessation of new lesion formation (p less than 0.001), maximum number of lesions (p = 0.019), and defervescence (p = 0.045). Mean constitutional illness score was significantly reduced on day 4 (0.5 vs 1.5, p = 0.05), as was the mean number of residual hypopigmented lesions present on 28-day follow-up examination (22.7 vs 92.7, p = 0.018). Two complications, both bacterial superinfections, occurred in placebo recipients. Adverse experiences and varicella-zoster virus antibody titers measured 28 days after enrollment were similar in both treatment groups. Comparison of placebo recipients with children 2 to 12 years of age participating in a companion study indicated that varicella is more severe in adolescents: mean maximum total lesions (421 vs 347, p = 0.003), mean maximum constitutional illness score (3.1 vs 2.2, p = 0.032), and mean number of residual lesions (92.7 vs 33.2, p = 0.01) were all greater in the adolescent population.Oral acyclovir therapy is safe and effective for treatment of varicella in otherwise healthy adolescents; this may be an appropriate subgroup for treatment with antiviral drugs because the disease is more severe in them than in younger children.

Abstract

Data obtained from neonates receiving zidovudine as part of a phase I study were used to estimate the population pharmacokinetic parameters of this drug and to determine the minimum number of data points necessary to provide accurate estimates of the kinetic parameters and their variability. Analysis was performed with 541 concentrations of zidovudine, obtained from 32 infants and with a variety of reduced data sets using NONMEM (nonlinear mixed effect model). The reduced data sets were derived by randomly reducing the number of sampling time points per dosing interval and/or by randomly reducing the number of available subjects. We determined that accurate estimates of pharmacokinetic parameters and their variability were obtained with the inclusion of all 32 patients using only two concentration-time points per dose interval, provided that one of the points was obtained during the first 2 h after administration of the drug. The parameters themselves were adequately estimated with only 24 subjects and two concentration-time points per dose interval. We suggest that NONMEM should be used in addition to the traditional pharmacokinetic analysis to obtain more precise information directly in the population of interest with a minimum of blood sampling from each patient. This is especially critical in infants whose blood volumes are limited.

Abstract

Although the antiviral agent ribavirin improves the course of lower respiratory tract disease in spontaneously breathing infants with respiratory syncytial virus infection, it is not known whether ribavirin can benefit infants with severe respiratory syncytial virus disease who require mechanical ventilation.We conducted a randomized, double-blind, placebo-controlled evaluation of ribavirin (20 mg per milliliter) administered continuously in aerosolized form to infants receiving mechanical ventilation for respiratory failure that was caused by documented respiratory syncytial virus infection.Of the 28 infants (mean [+/- SD] age, 1.4 +/- 1.7 months) enrolled, 7 had underlying diseases predisposing them to severe infection (mean age, 3.0 +/- 2.6 months), and 21 were previously normal (mean age, 0.8 +/- 0.9 month). Among the 14 infants who received ribavirin, the mean duration of mechanical ventilation was 4.9 days (as compared with 9.9 days among the 14 who received placebo; P = 0.01), and the mean length of supplemental oxygen use was 8.7 days (as compared with 13.5 days; P = 0.01). The mean length of the hospital stay was 13.3 days after treatment with ribavirin and 15.0 with placebo (P = 0.04). When only the 21 previously normal infants were considered, the mean length of the hospital stay was 9.0 days for the ribavirin recipients and 15.3 days for those who received placebo (P = 0.005).In infants who require mechanical ventilation because of severe respiratory syncytial virus infection, treatment with aerosolized ribavirin decreases the duration of mechanical ventilation, oxygen treatment, and the hospital stay.

Abstract

Respiratory viruses have been implicated in pulmonary exacerbations of CF and in the long-term course of pulmonary dysfunction in these patients. However, the data are by no means complete and there is the clear need for more intensive evaluations of the role of viral pathogens in this population. Further controlled prospective studies assessing the impact of viral infections in large cohorts of patients with CF are still necessary. Placebo-controlled, antiviral treatment protocols also should be initiated. In clinical practice at the present time, patients with CF should be assessed for respiratory viral infections, at least at the time of hospitalizations for pulmonary deterioration. This assessment should include obtaining specimens from the respiratory tract for viral cultures and rapid respiratory viral antigen detection. Identifying a respiratory viral infection may alter clinical care. The patient can be isolated appropriately, and it may be possible to reduce the intensive use of expensive and potentially toxic parenteral antibiotics. The role of antiviral therapy in these patients must await further evaluations. The mechanisms of the short- and long-term effects of respiratory viruses in patients with CF have not been defined. However, pathophysiologic studies conducted in normal children and adults allow the development of several plausible hypotheses. The definition of mechanisms of injury in this population must be a priority, since it may influence clinical practice. If airway obstruction is the principal mechanism of viral-induced injury, therapeutic approaches designed to relieve the obstruction would be most appropriate. For example, if the obstruction resulted from induced or aggravated reactive airway disease, the current common practice of prescribing chronic bronchodilator therapy would be appropriate. This therapy might be especially suited to those experiencing frequent viral infections. In addition, the administration of bronchodilators to patients during acute exacerbations of pulmonary disease caused by viruses might be of clinical benefit. If, on the other hand, the principal mechanism of viral-induced injury is found to be through synergistic interaction with bacteria, the current practice of aggressive antimicrobial therapy would remain appropriate.

Abstract

Despite the use of vidarabine, herpes simplex virus (HSV) infection in neonates continues to be a disease of high morbidity and mortality. We undertook a controlled trial comparing vidarabine with acyclovir for the treatment of neonatal HSV infection.Babies less than one month of age with virologically confirmed HSV infection were randomly and blindly assigned to receive either intravenous vidarabine (30 mg per kilogram of body weight per day; n = 95) or acyclovir (30 mg per kilogram per day; n = 107) for 10 days. Actuarial rates of mortality and morbidity among the survivors after one year were compared overall and according to the extent of the disease at entry into the study (infection confined to the skin, eyes, or mouth; encephalitis; or disseminated disease).After adjustment for differences between groups in the extent of disease, there was no difference between vidarabine and acyclovir in either morbidity (P = 0.83) or mortality (P = 0.27). None of the 85 babies with disease confined to the skin, eyes, or mouth died. Of the 31 babies in this group who were treated with vidarabine and followed for a year, 88 percent (22 of 25) were judged to be developing normally after one year, as compared with 98 percent (45 of 46) of the 54 treated with acyclovir (95 percent confidence interval for the difference, -4 to 24). For the 71 babies with encephalitis, mortality was 14 percent with vidarabine (5 of 36) and with acyclovir (5 of 35); of the survivors, 43 percent (13 of 30) and 29 percent (8 of 28), respectively, were developing normally after one year (95 percent confidence interval for the difference, -11 to 39). For the 46 babies with disseminated disease, mortality was 50 percent (14 of 28) with vidarabine and 61 percent (11 of 18) with acyclovir (95 percent confidence interval for the difference, -20 to 40); of the survivors, 58 percent (7 of 12) and 60 percent (3 of 5), respectively, were judged to be developing normally after one year (95 percent confidence interval for the difference, -40 to 50). Both medications were without serious toxic effects.In this multicenter, randomized, blinded study there were no differences in outcome between vidarabine and acyclovir in the treatment of neonatal HSV infection. The study lacked statistical power to determine whether there were sizable differences within the subgroups of those with localized HSV, encephalitis, or disseminated disease.

Abstract

In a controlled trial comparing acyclovir with vidarabine in the treatment of neonatal herpes simplex virus (HSV) infection, we found no significant difference between the treatments in adjusted mortality and morbidity. Hence, we sought to define for the entire cohort (n = 202) the clinical characteristics that best predicted the eventual outcome in these neonates.Data were gathered prospectively at 27 centers between 1981 and 1988 in infants less than one month of age who had virologically confirmed HSV infection. We examined the outcomes by multivariate analyses of 24 variables. Disease was classified in one of three categories based on the extent of the involvement at entry into the trial: infection confined to skin, eyes, or mouth; encephalitis; or disseminated infection.There were no deaths among the 85 infants with localized HSV infection. The mortality rate was significantly higher in the 46 neonates with disseminated infection (57 percent) than in the 71 with encephalitis (15 percent). In addition, the risk of death was increased in neonates who were in or near coma at entry (relative risk, 5.2), had disseminated intravascular coagulopathy (relative risk, 3.8), or were premature (relative risk, 3.7). In babies with disseminated disease, HSV pneumonitis was also associated with greater mortality (relative risk, 3.6). In the survivors, morbidity was most frequent in infants with encephalitis (relative risk, 4.4), disseminated infection (relative risk, 2.1), seizures (relative risk, 3.0), or infection with HSV type 2 (relative risk, 4.9). With HSV infection limited to the skin, eyes, or mouth, the presence of three or more recurrences of vesicles was associated with an increased risk of neurologic impairment as compared with two or fewer recurrences.

Abstract

Concern about neonatal herpes often leads to cesarean delivery of infants in women with a history of genital herpes. The antiviral drug acyclovir has been used effectively to suppress genital herpes simplex virus recurrences in nonpregnant adults. Its administration to pregnant women with recurrent genital herpes may reduce herpes simplex virus recurrences and thus may decrease the cesarean section rate among this population. To study the pharmacokinetics, safety, and patient tolerance of suppressive oral acyclovir, either 200 mg (n = 7) or 400 mg (n = 8) was administered orally every 8 hours to pregnant women with a history of recurrent herpes simplex virus, from 38 weeks' gestation until delivery. The mean +/- SD plasma levels for the 200 and 400 mg groups, respectively, were: first dose peak, 1.7 +/- 0.6 and 2.3 +/- 1.0 mumol/L; steady-state trough, 0.7 +/- 0.3 and 0.8 +/- 0.6 mumol/L; steady-state peak, 1.9 +/- 1.0 and 3.3 +/- 1.0 mumol/L. In late gestation maternal acyclovir pharmacokinetics were similar to those of nonpregnant adults from other studies. Acyclovir was concentrated in the amniotic fluid; however, there was no accumulation in the fetus (mean maternal/infant plasma ratio at delivery was 1.3). Acyclovir was well tolerated, and no toxicity was seen in the mothers or infants. The administration of acyclovir, 400 mg every 8 hours, appears appropriate for use in an efficacy and safety study regarding suppression of herpes simplex virus recurrences during the last weeks of pregnancy.

Abstract

The polymerase chain reaction was adapted to the amplification of a herpes simplex virus (HSV) DNA sequence, common to HSV types 1 and 2 (HSV-1, HSV-2). The amplified product was detectable by ethidium-bromide staining or Southern hybridization of gels and by dot hybridization. The HSV polymerase chain reaction detected HSV DNA in samples obtained from eight patients with genital lesions from which HSV-2 was isolated in tissue culture and from four patients with labial lesions from which HSV-1 was isolated. The HSV polymerase chain reaction identified HSV in clinical specimens obtained from 11 women who had asymptomatic genital HSV infections at delivery. None of 11 samples obtained at delivery from women who had antibodies to HSV-2, but whose delivery cultures were negative, were positive by polymerase chain reaction and no false-positive reactions were obtained when the reaction mixture contained human cell DNA or varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, or human papillomavirus DNA.

Abstract

We evaluated the effects of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics of gentamicin in 18 infants who underwent ECMO therapy for severe respiratory failure and received gentamicin for possible sepsis. Twelve of these infants continued to receive gentamicin after ECMO had been discontinued. The volume of distribution (Vd) of gentamicin in the newborns receiving ECMO was 0.58 +/- 0.04 liter/kg, compared with a Vd of 0.45 +/- 0.02 liter/kg after ECMO had been discontinued (P = 0.02). The clearance of gentamicin in the patients undergoing ECMO was 42 +/- 3 ml/kg/hour compared with 57 +/- 4 ml/kg/hour in those patients off ECMO (P = 0.003). The elimination half-life in patients receiving ECMO was 10.0 +/- 0.7 hours compared with 5.7 +/- 0.4 hours after ECMO had been discontinued (P less than 0.0001). Neonates undergoing ECMO demonstrate a higher volume of distribution of gentamicin, a lower clearance, and consequently a longer half life for this drug. We conclude that gentamicin and probably other aminoglycosides should be given at dose rates about 25% lower than usual and at longer dosing intervals in patients undergoing ECMO therapy.

Abstract

In order to study the epidemiology of herpes simplex type 2 (HSV-2) infections during pregnancy, we used an enzyme immunoassay to detect type-specific antibodies to HSV-2 glycoprotein G in serial blood samples obtained from a cohort of 1891 pregnant women. Blood samples obtained at about 17 and 32 weeks of gestation and at the time of delivery were assessed for antibody to HSV-2 glycoprotein G in order to evaluate the prevalence of past infections with HSV-2 and the rate of acquisition of HSV-2 infection during pregnancy. Three hundred eleven pregnant women (16.5%) were found to have had past infections with HSV-2. Four of the 1580 women who were initially seronegative developed antibodies to HSV-2 during pregnancy. The annualized rate of acquisition of HSV-2 infection in pregnant women was 0.58%. Three of four women had asymptomatic primary infections; all of the women had preexisting HSV-1 immunity. None of the women or their infants experienced any adverse consequences of gestational herpes. Based upon our very limited number of observations to date, asymptomatic primary episodes occurring in women with previous HSV-1 immunity may be of less consequence to the fetus and neonate than symptomatic true primary HSV-2 infections.

Abstract

The role of antiviral antibodies in protection against neonatal herpes simplex virus (HSV) infection remains controversial. The relationship between neonatal and maternal anti-HSV antibodies and disease presentation was analyzed in 47 babies. Of the neonates, 77% had localized and 23% had disseminated HSV infection. Antibody-dependent cellular cytotoxic (ADCC) antibodies were evaluated in comparison with HSV neutralizing antibodies. High maternal (greater than 1:10(4)) or neonatal (greater than 1:10(3)) anti-HSV ADCC antibody levels or high neonatal antiviral neutralizing levels (greater than 1:20) were independently associated with an absence of disseminated HSV infection. Cochran-Mantel-Haenszel analysis demonstrated that ADCC levels were associated with disease status (P less than .02) while controlling for the level of neutralizing antibody.

Abstract

The pharmacokinetics of vancomycin hydrochloride was studied in 12 very low birth weight infants. The gestational age (mean +/- SD) was 25.9 +/- 1.3 weeks and body weight was 769.2 +/- 151.5 g at the time of initiation of the study. Vancomycin was infused over a period of 60 minutes in a dosage of 14.2 +/- 3.2 mg/kg once daily in 10 patients, twice daily in 1 patient and every 36 hours in 1 patient for a mean of 10.5 +/- 4.9 days. Serial blood samples were obtained and the concentration time data were fitted to a one-compartment open model using the ADAPT computer program. A significant positive correlation was found between postconceptional age and vancomycin clearance (P less than 0.005) and between vancomycin elimination half-life and plasma creatinine (P less than 0.01). A negative correlation existed between plasma creatinine and vancomycin clearance (P less than 0.005), between postconceptional age and plasma creatinine (P less than 0.005) and between vancomycin half-life and postconceptional age (P less than 0.01). On the basis of these findings a vancomycin dosage of 15 mg/kg every 24 hours for infants less than 1000 g should yield concentrations within the accepted therapeutic range. This susceptible population requires frequent monitoring of vancomycin concentrations because of the high degree of interpatient variability and the continuous maturation of renal function.

Abstract

The pharmacokinetics and safety of amphotericin B infusion were studied in 13 infants and children (age range 3 weeks to 18 years; median age 11 years) treated with the drug for proved (n = 11) or suspected (n = 2) fungal infections. The dose during the first day was 0.5 mg/kg, followed by a daily dose of 1 mg/kg for the rest of the treatment period in most patients. The drug was infused over 4 to 6 hours. During the first day, serum concentrations were above the target therapeutic level of 0.3 microgram/ml in all patients at 2 and 6 hours from the start of the infusion, in 12 of 13 patients at 12 hours, but in only 6 of 13 patients at 24 hours. On the third day, all concentrations were greater than 0.3 microgram/ml throughout the 24-hour period, and in 12 of 13 patients were greater than 0.5 microgram/ml. The same kinetic profile prevailed on days 7 to 10 of therapy, with a tendency for increasing concentrations. Elimination half-life was 9.93 +/- 1.5 hours (mean +/- SEM), clearance rate 26 +/- 5 ml/kg.hr, and distribution volume 378 +/- 25 ml/kg. The half-life inversely correlated with patient's age. Pharmacokinetic values calculated during the first day were not different from those calculated on day 3. Significant decreases in hemoglobin, platelets, and serum potassium concentration were recorded along with significant increases in serum creatinine, urea, and aspartate transaminase values. Because of the large pharmacokinetic variability and the high rate of serious adverse effects, individualized dosing of amphotericin B based on therapeutic drug monitoring should be considered.

Abstract

We obtained specimens for viral culture from mothers, infants, or both at the time of 6904 deliveries, without regard to the mothers' history of genital herpes. Herpes simplex virus (HSV) was recovered in cultured specimens from 14 of the 6904 deliveries (0.20 percent); all 14 mothers were asymptomatic. All viral isolates were herpes simplex virus type 2 (HSV-2). Only 1 of the 14 women (7 percent) had a history of genital herpes, whereas 12 (86 percent) had serologic evidence of a previous infection with HSV-2. None of the infants born to these 12 women contracted neonatal herpes. However, one of the two infants born to women with serologic evidence of a primary HSV infection at the time of delivery contracted neonatal herpes. Our findings show that most infants at risk of exposure to HSV at delivery will not be identified if concern about asymptomatic shedding of virus is limited to women with a history of genital herpes infection. Most neonatal exposure to an asymptomatic maternal HSV infection at delivery is not predictable or preventable. Therefore, physicians caring for newborns need to consider neonatal herpes in the differential diagnosis when infants become ill during the first weeks of life, regardless of the presence or absence of identifiable risk factors for HSV infection.

Abstract

We used a murine monoclonal antibody to herpes simplex virus (HSV) type 2 (HSV-2) glycoprotein G (gG) to develop an enzyme immunoassay that detected HSV-2 type-specific antibodies in human sera. Antibodies to HSV-2 gG were detected in 98 (96%) of 102 sera from pregnant women with culture-proved HSV-2 infection. Sixty-five percent of the women had serological evidence of past HSV-2 infection by the Rawls index, based on titers of neutralizing antibody to HSV type 1 and HSV-2. Thirty (88%) of 34 infants exposed to maternal HSV infection at delivery had antibodies to HSV-2 gG and remained well. One infant exposed to primary maternal HSV-2 infection lacked antibodies to HSV-2 gG and developed neonatal HSV-2 infection. The mean +/- SD optical density by HSV-2 gG enzyme-linked immunosorbent assay for sera obtained from 17 infants within one week after onset of neonatal HSV-2 infection was 0.25 +/- 0.12, compared with 1.15 +/- 0.34 in cord blood sera from exposed infants who did not develop symptoms (P less than .0001 by t test).

Abstract

In comparison to older children and adults, neonates are immunologically incompetent. They are susceptible to infections caused by a variety of microorganisms, including bacteria, fungi and viruses. These infectious agents may be acquired by neonates either prenatally, during the intrapartum period or postnatally. The purpose of this review is to emphasize the potential impact of viral infections contracted by neonates at the time of delivery or within the neonatal period. The viruses reviewed include the herpes group of viruses (cytomegalovirus, herpes simplex viruses and varicella-zoster virus), type B hepatitis virus, human immunodeficiency virus, respiratory viruses, enteroviruses, rotavirus and human papilloma virus. For each virus the potential sources and incidence of the infection, the common manifestations of the illness, and possible means of prevention and therapy are discussed. Although infections caused by bacteria tend to be more clinically dramatic and more immediately life-threatening, it is emphasized that infections caused by viruses are common and associated with substantial long-term morbidity. Perinatal viral infections need to be recognized as early in life as possible so that their natural history can be more completely defined and any possible intervention made.

Abstract

Respiratory deterioration accounts for the morbidity and mortality observed in patients with cystic fibrosis. The role of Legionella in this deterioration was determined in a 2-year prospective study of 49 patients with cystic fibrosis and 19 sibling controls. Sera were obtained from participants on enrollment and at quarterly intervals. Legionella antibodies were measured in parallel using an indirect fluorescent assay. No seroconversions were observed. Eleven of 49 patients with cystic fibrosis (22%) were seropositive compared to none of 19 siblings (P less than 0.05). Six of the 11 patients demonstrated high titers (greater than or equal to 1:512) that persisted throughout the study. Absorption with pools of various Pseudomonas species reduced the antibody titers such that only 3 remained positive after absorption. Legionella was not found to be an important cause of clinical deterioration during this study. The results of the absorption studies suggest that high titers to Legionella in this population are due to cross-reacting antibodies.

Abstract

We studied the risk of herpes simplex virus (HSV) infections in neonates exposed to HSV at the time of vaginal delivery to mothers with a history of recurrent genital HSV infections. None of 34 infants exposed to HSV type 2 acquired an HSV infection. On the basis of this sample, the 95 percent confidence limit for the theoretical maximum infection rate is 8 percent. Cord blood or blood obtained during the first two weeks of life was available from 33 of the 34 exposed, uninfected neonates. All 33 of the samples possessed demonstrable neutralizing antibody to HSV type 2, and 79 percent had titers above 1:20. These results were compared with those in a previously studied group of neonates with HSV infections; the latter infants were significantly less likely at the onset of symptoms to have demonstrable neutralizing antibody to HSV type 2 (P = 0.000148) or to have titers above 1:20 (P less than 0.00001). We conclude that given the low attack rate, empirical antiviral therapy is not warranted in all infants of mothers with recurrent genital HSV infection who are exposed to the virus in the birth canal. Our findings suggest that the presence and titer of neutralizing antibody to HSV contribute to the low attack rate.

Abstract

The pharmacokinetics of intravenous vancomycin was studied in 20 preterm infants (gestational age, 26.5 weeks +/- 2.6 weeks [standard deviation]; birthweight, 880 +/- 340 g). At the time of the studies their postconceptional age was 36.4 +/- 4.5 weeks. The drug was infused over 30 min in a dose between 9.2 and 18 mg/kg. A highly significant correlation existed between postconceptional age or body weight and vancomycin t1/2 and clearance. Serum creatinine concentrations correlated with vancomycin t1/2 and clearance. Serum creatinine tended to decrease with increasing postconceptional age. Based on the excellent correlation between age (or weight) and vancomycin pharmacokinetics, dose and dose-interval recommendations are presented.

Abstract

In 414 pregnant women with a history of recurrent genital herpes simplex infection, we studied the correlation between asymptomatic viral shedding in late pregnancy and at the time of delivery. Antepartum cultures for asymptomatic reactivation of herpes simplex virus were positive in 17 of the 414 women (4.1 percent). None of these women had positive cultures at the time of delivery. Cultures of specimens obtained at delivery from 5 of 354 asymptomatic mother-infant pairs (1.4 percent) were positive for asymptomatic excretion of herpes simplex virus. None of these women had had antepartum cultures that documented asymptomatic excretion of herpes simplex virus, despite the fact that culturing was repeatedly performed during the four weeks before delivery. Asymptomatic shedding of herpes simplex virus occurred with the same frequency at delivery, whether or not any episodes of symptomatic recurrence were noted during the pregnancy (1.4 vs. 1.3 percent). We conclude that antepartum maternal cultures do not predict the infant's risk of exposure to herpes simplex virus at delivery.

Abstract

We carried out a nonrandomized, unblinded study to compare the efficacy of rifampin alone with that of rifampin in combination with trimethoprim in the eradication of the Haemophilus influenzae type b (HIB) carrier state among contacts of patients with invasive HIB infection. The study population comprised 17 index patients admitted to hospital with severe HIB infections and 233 contacts, 43 of whom had nasopharyngeal colonization with HIB of the same biotype as that of the index patient. Rifampin in a daily dose of 20 mg/kg (maximum 600 mg) for 4 days eradicated the carrier state in 86% of cases, as did the combination of rifampin at the same dosage and trimethoprim in a daily dose of 5 mg/kg (maximum 160 mg) for 4 days.

Abstract

The sequelae of acute bacterial meningitis in children who were treated with ampicillin or chloramphenicol for seven days during the period January 1979 to June 1983 were assessed prospectively. The 235 patients (117 boys and 118 girls) ranged in age from four days to 18 years (mean 26.4 months). Haemophilus influenzae type b was isolated in 70% of patients, Streptococcus pneumoniae in 20%, and Neisseria meningitidis in 10%. The mortality rate was 6.4%. No relapses occurred. Of the 220 survivors, 171 had neurologic psychometric, audiologic, and ophthalmologic assessments performed for a minimum of 1 year following their illness. One hundred thirty-six (80%) children had no detectable sequelae; 20% had mild to severe handicaps. The frequency of sequelae was greatest among children with S pneumoniae meningitis (57%) and least among children with N meningitidis (0%). The sequelae observed included: sensorineural hearing loss (12.9%), developmental delay (5.3%), speech defect (4.7%), motor defect (3.0%), hydrocephalus (1.7%), and seizure disorder (1%). The frequency of observed sequelae among these patients is similar to that previously reported in children treated for ten to 14 days. Our findings indicate that seven days of intravenous antibiotic therapy is adequate for the treatment of bacterial meningitis in children.

Abstract

We assessed the value of 41 skin biopsy specimens obtained from 32 immunocompromised patients with fever and neutropenia. Fifty-six percent (23/41) of these biopsy specimens resulted in a specific diagnosis. These diagnoses included infection in 12 cases, graft-vs-host disease in nine, leukemic infiltrate in one, and drug reaction in one. The remaining 18 biopsy specimens showed either nonspecific changes or normal tissue. The infectious agents identified included Aspergillus in nine patients, Candida in three patients, and Staphylococcus aureus in one patient. As a result of the biopsy findings, therapy was altered in 49% (20/41) of the cases. The most frequent therapeutic change was initiation of amphotericin B for a demonstrated fungal infection. We found skin biopsies to be a valuable diagnostic tool in the assessment of the febrile, neutropenic, immunocompromised patient with skin lesions.

Abstract

Coagulase-negative staphylococci (CONS) are occasionally cultured from foci of osteomyelitis in otherwise healthy individuals and are usually regarded as contaminants. The present report describes two children with subacute osteomyelitis of the distal tibia in which pure cultures of CONS were obtained from bone. In one patient, the infection was multifocal, and CONS were isolated from two anatomical sites at two different times. In the other patient, the infection was unifocal, and CONS were cultured from two separate specimens obtained from the same site. In both patients, the symptoms progressed until appropriate antibiotic treatment was initiated. CONS isolated from cultures of bone should not automatically be disregarded. Appropriate antibiotic therapy may result in clinical resolution.

Abstract

Dactylitis commonly occurs in patients with homozygous hemoglobin S disease (sickle cell anemia), sickle cell-hemoglobin C disease or sickle cell-beta-thalassemia. A case is reported of dactylitis associated with sickle cell trait, a very rare occurrence. It may be that in this patient the disorder was secondary to severe diarrhea and dehydration.

Abstract

Bacterial infections in the newborn are associated with significant morbidity and mortality. Compared to older children, neonates are immuno-compromised hosts and clinical manifestations of infection are more subtle. Empiric therapy is mandatory when bacterial infection is suspected. Eight basic principles governing the use of antibiotics in the newborn are discussed.

Abstract

Twenty clinical isolates of Haemophilus influenzae type b were used to determine the in vitro interactions of rifampin with ampicillin or chloramphenicol. Potential interactions of the drugs were evaluated by calculating the fractional inhibitory concentration index and fractional bactericidal concentration index for each strain after treatments with the drugs alone and in combination. There was no evidence of synergy or antagonisms between ampicillin and rifampin or between chloramphenicol and rifampin. With ampicillin-susceptible H. influenzae type b strains, an additive effect was observed with seven strains, and an indifferent effect was observed with three strains. Similarly, with chloramphenicol-susceptible H. influenzae type b strains, an additive effect was observed with eight strains, and an indifferent effect was observed with two strains.

Abstract

The prevalence of Pseudomonas cepacia infection increased from 10% in 1971 to 18% by 1981 in a population of approximately 500 patients with cystic fibrosis. Carriage of P. aeruginosa has remained unchanged at 70% to 80% over the same period. Patients infected with P. cepacia have greater impairment of pulmonary function than those with P. aeruginosa. A syndrome characterized by high fever, severe progressive respiratory failure, leukocytosis, and elevated erythrocyte sedimentation rate has occurred in eight patients over the past 3 years, with a 62% fatality rate. Because P. cepacia strains are uniformly resistant to ticarcillin, piperacillin, and aminoglycosides, and because ceftazidime is ineffective despite in vitro activity, treatment of these infections is very difficult. Prevention of acquisition and effective treatment of P. cepacia in patients with cystic fibrosis are now major clinical problems in our clinic.

Abstract

The nephrotoxicity of gentamicin and amikacin was compared during presumed sepsis in 107 premature neonates. To examine the possibility that nephrotoxicity was directly associated with the clinical conditions of "sepsis," a control group of 26 chloramphenicol-treated newborns was also studied. Two markers of proximal renal tubular injury, N-acetyl-beta-glucosaminidase (NAG) and beta 2-microglobulin, were measured in 6-hr aliquots of urine. Because urine creatinine excretion increased with postconception age, markers were expressed in terms of excretion rate rather than per milligram of creatinine. The NAG excretion rate was significantly higher in gentamicin-treated patients (138 +/- 10 U/min, mean +/- SE) than in amikacin-treated patients (85 +/- 7 U/min) but did not differ between patients treated with amikacin and those treated with chloramphenicol (81 +/- 11 U/min). Excretion of beta 2-microglobulin did not differ among the three patient groups. We conclude that amikacin may be less nephrotoxic than gentamicin in the premature newborn.

Abstract

In a two-year prospective study, we examined the effect of respiratory viral infections on pulmonary function in 49 patients with cystic fibrosis (mean age, 13.7 years). Nineteen normal siblings (mean age, 14) served as controls. Subjects were assessed quarterly and at the time of any respiratory illness. Each assessment included nasal washes for viral isolation and blood drawing for respiratory viral serologic studies. Pulmonary-function tests were performed at least twice yearly. Respiratory illnesses were reported significantly more often in the patients (3.7 per year) than in the normal siblings (1.7 per year), although the frequency of proved viral infections (1.67 per year) was identical. In the patients with cystic fibrosis significant correlations (P less than 0.0001) were found between the annual incidence of viral infections and every measure of disease progression in the two-year period, including the rate of decline of the Shwachman score (r = 0.71), the percentage of ideal weight for height (r = 0.80), the forced vital capacity (r = 0.85), the forced expiratory volume in the first second (r = 0.84), the forced midexpiratory flow rate (r = 0.68), and the frequency (r = 0.53) and duration (r = 0.84) of hospitalizations for respiratory exacerbations. We conclude that frequency of viral respiratory infections is closely associated with pulmonary deterioration in patients with cystic fibrosis.

Abstract

We conducted a randomized, double-blind, placebo-controlled study during a 30-month period to determine whether sulfamethoxazole and trimethoprim would decrease the incidence of infections occurring after ventriculoperitoneal shunt surgery. Of the 120 patients who completed the study according to protocol, 55 received sulfamethoxazole and trimethoprim and 65 received placebo. The incidence of CSF infection in the group receiving sulfamethoxazole and trimethoprim (4/55) was similar to that in the control group (5/65). There was a trend toward earlier identification of infections in the sulfamethoxazole and trimethoprim group (mean, 24.5 days) compared with the control group (mean, 47 days). There was no difference between infected and uninfected patients with respect to frequency of purported risk factors for infection, including history of shunt infection, history of recent myelomeningocele repair, and type and duration of shunt surgery. The incidence of shunt malfunction was similar in uninfected patients receiving antibiotic prophylaxis (18/51) compared with that of patients receiving placebo (23/60). We did not find that the perioperative use of sulfamethoxazole and trimethoprim reduced the incidence of shunt infection or malfunction.

Abstract

Catheter-associated infection is a frequent complication in patients with indwelling intravenous catheters used for administration of total parenteral nutrition and/or cancer chemotherapy. Thirty-seven catheter-associated infections in 19 patients were identified in our retrospective survey conducted for the period from January 1, 1982, through December 31, 1982. Fourteen patients were receiving total parenteral nutrition for gastrointestinal disorders, and five were receiving total parenteral nutrition and chemotherapy for underlying malignancy. Coagulase-negative staphylococci were isolated from 65% of catheter-associated bacteremias, as a single species (18 cases) or as one of multiple species (6 cases). Ten of 33 coagulase-negative staphylococcal isolates (30%) were methicillin-resistant. Twenty-one infections (57%) were initially treated with antibiotics administered through the central venous catheter. There were three failures with this treatment; in two cases the catheter was removed because of continued fever and positive blood cultures despite antibiotics, and one patient developed a pyogenic granuloma. The remaining 18 (86%) catheter-associated infections were cured without catheter removal. However, a new infection occurred subsequently in two of these patients. We recommend that vancomycin and an aminoglycoside be the initial empiric therapy for suspected catheter-associated sepsis. Lack of defervescence or continued positive blood cultures for 2 to 4 days despite antibiotics are indications for catheter removal. Otherwise antibiotics should be continued for 14 to 21 days.

Abstract

We assessed the diagnostic value of 46 open lung biopsies performed on 44 immunocompromised children with acute pulmonary infiltrates. We assessed also how frequently the results of these biopsies resulted in a change of therapy. A histological diagnosis was established for all of our patients. At least one infectious agent was found in 72% of the specimens. Nonspecific interstitial pneumonitis was observed in 24%, and two biopsy specimens demonstrated relapsed malignancy. In this series, the empirically chosen preoperative therapy was altered on 30 (65%) of 46 occasions. Specific therapy, not provided before surgery, was initiated in 26% of our patients, and broad-spectrum preoperative therapy was discontinued in 43%. Open lung biopsy is a valuable diagnostic procedure in the immunocompromised host with pulmonary infiltrates.

Abstract

A high-performance liquid chromatographic method for the analysis of amphotericin B in 25 microliters of serum or plasma is described. The procedure involves the addition of the internal standard, p-nitrobenzyloxyamine, to the sample followed by a precipitation of protein with acetonitrile. The supernatant is directly injected into a chromatograph attached to a reversed-phase mu Bondapak (Waters) column containing C18 packing. The mobile phase is a 60 : 40 mixture of a sodium acetate buffer (10 mM, pH 7.0)--acetonitrile, and we employ a flow-rate of 1.5 ml/min and a detection wavelength of 405 nm. Total analysis time per sample is 10 min. Coefficients of variation were found to be less than 4% for concentrations less than 2 mg/l. Analytical recoveries were between 75 and 80%. No drug or drug metabolite interference was found. The method will be used to study pharmacokinetic and pharmacodynamic data in a pediatric population.

Abstract

Ventricular cerebrospinal fluid (CSF) trimethoprim-sulphamethoxazole (TMP-SMZ) concentrations were measured in 15 patients. At varying times, not exceeding eight hours prior to surgery, each patient received a dose of 5 mg/kg TMP with 25 mg/kg SMZ as a 1 h intravenous infusion. The mean ventricular CSF TMP concentration was 1.1 mg/l with a range of 0.5-3.2 mg/l. The SMZ concentration was 17.9 mg/l with a range of 5-40 mg/l. There was no apparent relationship between achievable CSF concentrations and the time elapsed after drug administration. The CSF concentrations were achieved despite the lack of meningeal inflammation. In 11 of 14 patients, the levels exceeded the minimum inhibitory concentrations for Staphylococcus aureus and Staph. epidermidis.

Abstract

We studied pharmacokinetics of chloramphenicol in 9 neonates having a mean gestational age of 31.2 +/- 1.9 weeks (mean +/- SEM). The studied dose was the final dose of treatment in 8 of these and the first dose in 2 of these. 1 neonate was studied twice. Concentrations of chloramphenicol and its 3-monosuccinate and 1-monosuccinate esters were measured in serum by high performance liquid chromatography. Apparent total body clearance of chloramphenicol correlated with postnatal age (r = 0.81, p less than 0.01). Mean apparent clearance was 1.1 ml X min-1 X kg-1. Serum concentrations of succinate esters were below assay sensitivity after 6 h postdose. Factors leading to excessive chloramphenicol concentrations (greater than 25.0 mg/l) were evaluated in another 44 newborns. Instability of the patient's clinical condition was an important cause of excessive serum concentrations during ongoing therapy.

Abstract

Antibody responses (as measured by radioimmunoassay), alterations in serum levels of complement, and the presence of circulating immune complexes (as measured by the fluid-phase C1Q-binding assay, the fluid-phase conglutinin assay, and the activation of C1 were evaluated in 15 children after meningitis and/or bacteremia caused by Streptococcus pneumoniae. The ages of the children ranged from two months to 16 years; the duration of follow-up ranged from 18 to 189 days (mean, 78 days). Increases in levels of homotypic antibody were found in only three (25%) of the 12 children in whom this response could be assessed, and all of these responses were transient. Eight (53%) of the 15 children had evidence of a heterotypic antibody response to S pneumoniae serotypes other than those causing their infections. The activation of C1 and C1q-binding activity were detected at the early stage of disease and were generally transient. The result of the fluid-phase conglutinin assay was positive for 14 (93%) of the 15 children later in the course of disease; this result was consistently positive throughout the follow-up period in the majority of children. Depressed concentrations of C4 were noted in nine children, depressed levels of C3 in four, and depressed levels of factor B in two.

Abstract

Meningitis due to Haemophilus influenzae serotype b biotype II occurred in a 2-year-old child who attended a nursery school along with 26 other 2-year-old children. Nasal swabs from these 26 contacts revealed a H influenzae type b colonization rate of 50% (13/26); simultaneously performed throat swabs detected a colonization rate of 4% (1/26). Biotyping of the H influenzae type b isolates revealed that only 46% (6/13) were the same biotype as the index case; the remaining seven isolates were biotype III. All children received treatment with 20 mg/kg/day of rifampin administered by the nursery school attendant as a single dose for four days before the results of the cultures were known. Eradication of H influenzae type b carriage was successful in three of the six biotype II carriers and five of the six biotype III carriers available for follow-up culture. It was concluded that: (1) the culture site utilized in determining H influenzae type b colonization rates may markedly influence the results obtained; (2) biotyping may be a valuable epidemiologic tool in investigating the contacts of patients with H influenzae type b disease, and (3) failures of rifampin to eradicate the carriage of H influenzae type b from the nasopharynx may occur. The prudent approach to the management of young contacts of patients with serious H influenzae type b disease is to recognize their high risk status and to maintain close surveillance of them. The role of chemoprophylaxis with rifampin remains to be established.

Abstract

A randomized double-blind, placebo-controlled, multicenter investigation assessed the usefulness of acyclovir in the treatment of immunosuppressed children with chickenpox. Twelve patients received placebo and eight received acyclovir. If the event of clinical deterioration, patients could be removed from the study to receive acyclovir. Eighteen patients had skin lesions within 96 hours of admission to the study. Nineteen patients had malignancies. The two groups of patients were similar in age, in concomitant or preceding immunosuppressive therapy, in status of malignancy, and in presenting granulocyte and lymphocyte counts. Zoster immune globulin or plasma had been given to 50% of the placebo group but to only 25% of the acyclovir group. One patient in each group had pneumonitis at entry. Of the patients without pneumonitis at entry, five of the 11 placebo patients compared with none of the seven acyclovir patients developed pneumonitis during treatment (P = 0.054). No evidence of toxicity related to acyclovir was observed.

Abstract

To evaluate the ability of a loading dose of chloramphenicol succinate to rapidly, achieve adequate serum concentrations of chloramphenicol, we compared two intravenously administered dosages of chloramphenicol succinate given to initiate treatment. Thirteen premature neonates received an initial dose of 12.5 mg/kg; 26 received a loading dose of 20 mg/kg. Capillary blood samples were obtained at two, four, and 12 hours after the first dose. After the dose of 12.5 mg/kg, 45% of the neonates did not achieve serum concentrations greater than 10 mg/L. After the loading dose of 20 mg/kg, all neonates achieved concentrations greater than 10 mg/L. The peak chloramphenicol concentrations after the 12.5 mg/kg dose was 8.8 +/- 11.2 mg/L (+/- SEM) and after the 20 mg/kg loading dose, 15.9 +/- 0.7 mg/L. The disposition of chloramphenicol was age dependent. Chloramphenicol concentration peaked at four hours in neonates less than or equal to 2 days postnatal age and at two hours in neonates 3 to 55 days postnatal age. Chloramphenicol succinate concentrations were greater in younger than in older neonates at both two and four hours after the dose. We conclude that a loading dose is appropriate when using chloramphenicol succinate in neonates.

Abstract

Transfusion-acquired cytomegalovirus infections occurred in 13.5% of 74 infants of seronegative mothers who were exposed to one or more blood donors who had a CMV indirect hemagglutination titer of 1:8 or higher. None of 90 infants of seronegative mothers exposed only to donors with CMV IHA titers of less than 1:8 became infected. Ten of 41 (24%) infants of seronegative mothers who received more than 50 ml of packed red blood cells and who were exposed to at least one seropositive donor became infected. None of 23 infants of seronegative mothers who received this amount of blood but who were exposed only to seronegative donors became infected. Fatal or serious symptoms developed in 50% of the infected infants of seronegative mothers and in none of the 32 infected infants of seropositive mothers. Acquired CMV infections occurred in 15% of infants of seropositive mothers who were exposed to the red blood cells of seropositive donors and in 17.6% of infants of seropositive mothers exposed only to seronegative donors. Use of seronegative donors reduced the prevalence of excretion of CMV among hospitalized infants who were 4 weeks of age or older from 12.5 to 1.8% and eliminated acquired CMV infections in infants of seronegative mothers.

Abstract

Eikenella corrodens is a slow-growing, Gram-negative, facultative, anaerobic organism that is normally found among oropharyngeal flora. Its isolation as a pathogen is increasingly being reported. Although well documented in the literature on adults, few cases of E corrodens infection have been reported in children. We describe two children with E corrodens pneumonia and empyema. In one, infection was mixed, but in the other the organism was isolated in pure culture. Both patients recovered after therapy with a combination of an antibiotic active in vitro against the organism, and surgical drainage. The diagnosis, bacteriology, and evidence for potential pathogenicity of the organism are reviewed; E corrodens should be considered as a potential pathogen, especially in predisposed patients.

Abstract

A micromethod for performance of the serum bactericidal test is described, and the results obtained with this method are compared with those obtained with the standard tube dilution macromethod. An agreement within +/- 1 dilution was achieved in 23 of 25 (92%) determinations of the serum bactericidal titer. The micromethod used approximately one-third of the amount of pooled normal human serum and of the technician's time required for performance of the macromethod. The micromethod offers an accurate and economical alternative to the macromethod for the performance of the serum bactericidal test and is particularly useful with infants and children since it minimizes blood loss.

USE OF THE SERUM BACTERICIDAL TITER TO ASSESS THE ADEQUACY OF ORAL ANTIBIOTIC-THERAPY IN THE TREATMENT OF ACUTE HEMATOGENOUS OSTEOMYELITISJOURNAL OF PEDIATRICSProber, C. G., YEAGER, A. S.1979; 95 (1): 131-135

Abstract

Serum bactericidal titers against Staphylococcus aureus were measured in 63 children who were receiving mafcillin or methicillin intravenously, or dicloxacillin, penicillin, or cephalexin orally. The SBTs obtained following unit does of 25 mg/kg of dicloxacillin, 35 mg/kg of penicillin, or 25 mg/kg of cephalexin with probenecid were comparable to those seen following intravenous doses of 40 mg/kg nafcillin or methicillin. Twenty-two children with acute hematogenous osteomyelitis proven or presumed to be due to S. aureus were treated intravenously until point tenderness and fever had resolved, and then with oral therapy. The mean duration of intravenous therapy was 14 days. Oral doses were adjusted so that a peak SBT of greater than or equal to 1:16 and a trough SBT of greater than or equal to 1:2 were obtained in most children. No recurrences occurred. The SBT proved to be a practical means of assessing the adequacy of oral therapy in children with infections due to S. aureus.

Abstract

The purpose of this study was to assess the usefulness of the white cell ratio of immature neutrophils (PMNs) to total (immature plus mature) PMNs as an indication of infection in the very small premature infant. We retrospectively reviewed the charts of 59 premature infants less than or equal to 1,250 g admitted to our Newborn Intensive Care Unit over a one-year period who had at least one white count determined. Twenty-three were born after rupture of membranes for greater than or equal to 24 hours (PROM), 47 had a one-minute Apgar score less than or equal to 6 and 31 had a five-minute Apgar scores less than or equal to 6, 38 had respiratory distress syndrome (RDS), and 4 had confirmed infection. Thirty-one of the infants had a ratio greater than or equal to .15 in the first day of life, a value which has been suggested in the literature as being abnormal and an indication to suspect sepsis. This ratio bore no statistical relationship to PROM, low Apgar scores, or RDS. We analyzed these same relationships using a ratio greater than or equal to .25, another ratio derived from data in the literature which has been said to suggest infection. No statistical correlation was found for low Apgars or RDS, but there was a significant relationship between PROM and attainment of a ratio greater than or equal to .25 (p less than .005). It is notable that 2 out of the 4 infants with infection had a ratio less than .15. We wish to cast doubt on the applicability of the currently defined WBC ratios in the literature as they apply to the infant with birth weight less than 1,250 g and emphasize the apparent effect of PROM as a factor upon these ratios.

Abstract

Tryptic soy broth and brain-heart infusion broth maintained herpes simplex virus within +/- 1 serial dilution of the original titer in all of 51 samples held for one to three days at 4 C. In contrast, holding temperatures of -20 C or 22 C resulted in losses of titer of 10(2) or more. Holding periods as long as five days prior to inoculation did not delay the appearance of the cytopathic effect following inoculation. Unmodified tryptic soy broth or brain-heart infusion broth and holding periods as long as three days at 4 C prior to arrival in the laboratory give as satisfactory results as do traditional viral culture media and prompt inoculation of the specimen.

Abstract

Yersinia pseudotuberculosis septicemia and postdiarrheal hemolytic-uremia syndrome (HUS) developed in a 15-month-old boy after he ingested unpasteurized goat's milk. The epidemiology of this organism and the disease states caused by it are discussed with the suggestion that an association between it and some cases of the HUS might be found if sought.